CHAMP: The Childhood and Adolescent Migraine Prevention Study

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01581281
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 488
• Locations: 35
• Arms: 3
• Duration (Months): 43
• Patients Per Site: 13.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this research study is to test two medicines for migraine prevention in children and adolescents.

Condition or Disease	Intervention/Treatment	Phase
Migraine; Migraine Disorders; Headache	Drug: Amitriptyline; Drug: Topiramate; Drug: Placebo	Phase 3

Detailed Description

The purpose of this research study is to test two medicines for migraine prevention in children and adolescents. The investigators want to see if amitriptyline and/or topiramate are better than placebo (sugar pill) in reducing headache frequency in children and adolescents ages 8 to 17 with migraines. At this time, there are no FDA approved medicines approved in the US for the prevention treatment of migraine headaches in children and adolescents.

Study Design

• Study Type: Interventional
• Actual Enrollment: 488 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Amitriptyline and Topiramate in the Prevention of Childhood Migraine
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Amitriptyline Drug to be administered twice daily.	Drug: Amitriptyline; Amitriptyline will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. The morning dose is a placebo pill. Dosing of amitriptyline will be weight-based.
Active Comparator: Topiramate Drug to be administered twice daily.	Drug: Topiramate; Topiramate will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. Dosing of topiramate will be weight-based.
Placebo Comparator: Placebo To be administered twice daily.	Drug: Placebo; Placebo will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance period.

Outcome Measures

Primary Outcome Measures

1. Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days [4 week baseline period and last 4 weeks of the 24-week trial]

   The primary endpoint was a ≥ 50% reduction in headache frequency from the 28 days (4 weeks) baseline period prior to randomization to the last 28 days (4 weeks) of the trial. Headache frequency was defined as the number of days with headache for a given four week 28 day (4 week) period. A headache day was defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each participant, the primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period. Results were compared across the three treatment groups.

Secondary Outcome Measures

1. Change in Absolute Headache Disability Score on PedMIDAS [baseline and 24 week endpoint]

   The PedMIDAS scale which evaluated the impact of headaches in school, home, play, and social activities, is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions were answered by the youth in consultation with their parents and reviewed by study staff. The PedMIDAS scale was administered at baseline (covering the three months prior to enrollment) and at the 24-week endpoint visit (the end of the maintenance period, covering three months of enrollment). A total PedMIDAS score (sum of items 1-6) was used in this trial. Scores range from 0-240; with a score of 0-10 indicating no disability, 11-30 mild disability, 31-50 moderate disability, and more than 50 severe disability in daily activities. The main outcome measure for this comparison will be the difference in the baseline and endpoint (24 week) PedMIDAS total scores for: Amitriptyline vs. Placebo Topiramate vs. Placebo Amitriptyline vs Topiramate

2. Change in Number of Headache Days [4 week baseline period and last 4 weeks of the 24-week trial]

   This outcomes measure examines whether the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This was assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. The change in absolute headache days was compared between: Amitriptyline vs. placebo Topiramate vs. placebo Amitriptyline vs. Topiramate

3. Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase [24 weeks]

   To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups.

4. Occurrence of Treatment Emergent Serious Adverse Events [24 weeks of the trial]

   To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Migraine with or without aura (International Classification of Headache Disorders, 2nd Edition (ICHD-II) or chronic migraine (ICHD-II revised)

• Migraine frequency based upon prospective headache diary of 28 days must be ≥ 4. Migraine frequency defined as any migraine during one day in the 28 day baseline period (1)

• PedMIDAS Disability Score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy

• Females or males 8-17 years, inclusive

1. Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine.

Exclusion Criteria:

• Continuous migraine defined as an unrelenting headache for a 28 day period

• Weight less than 30 kg or greater than 120 kg

• Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medications such as triptans more than 6 times per month

• Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that medication before entering the screening phase, or the use of Botulinum toxin (Botox®) within 3 months of entering the screening phase

• Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at doses recommended for migraine relief because of lack of efficacy or adverse events(2)

• Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs

• Known history of allergic reaction or anaphylaxis to AMI or TPM

• Abnormal findings on ECG at baseline, particularly lengthening of the QT interval greater than or equal to 450 msec

• Subject is pregnant or has a positive pregnancy test

• Subject is sexually active and not using a medically acceptable form of contraception

• Diagnosis of epilepsy or other neurological diseases

• History of kidney stones

• Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit (3)

• Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial

• Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient from being a suitable candidate for the study or interfere with the medical care needs of the study subject

(2)"Previously failed an adequate trial of AMI or TPM" is defined as: dosage of 1mg/kg/day of AMI or 2 mg/kg/day of TPM; trial of at least 3 months duration; efficacy of having at least a 50% decrease in migraine frequency in response to drug therapy; or unable to tolerate taking the medication due to treatment-related side effects.

(3)Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Medical Group	Phoenix	Arizona	United States	85016
2	University of California-San Francisco Headache Center	San Francisco	California	United States	94115
3	Stanford Hospital and Clinics	Stanford	California	United States	94305
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Colorado Springs Neurological Associates	Colorado Springs	Colorado	United States	80907
6	Children's National Medical Center	Washington, D.C.	District of Columbia	United States	20010
7	Premiere Research Institute	West Palm Beach	Florida	United States	33407
8	Atlanta Headache Specialists	Atlanta	Georgia	United States	30342
9	Josephson Wallack Munshower Neurology Research	Indianapolis	Indiana	United States	46237
10	Children's Mercy Hospital	Kansas City	Kansas	United States	66160
11	University of Louisville Health Sciences Center	Louisville	Kentucky	United States	40292
12	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
13	Children's Hospital of Boston	Waltham	Massachusetts	United States	02453
14	New England Regional Headache Center	Worcester	Massachusetts	United States	01605
15	Mayo Clinic	Rochester	Minnesota	United States	55905
16	Saint Louis University	Saint Louis	Missouri	United States	63104
17	University of Nevada	Reno	Nevada	United States	89502
18	Dent Neurological Institute	Amherst	New York	United States	14226
19	Winthrop University Hospital	Mineola	New York	United States	11501
20	The Headache Institute at Roosevelt Hospital	New York	New York	United States	10019
21	Schenectady Neurological Constultants, PC	Schenectady	New York	United States	12308
22	Akron Children's Hospital	Akron	Ohio	United States	44308
23	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
24	The Children's Hospital, Cleveland Clinic	Cleveland	Ohio	United States	44195
25	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
26	Oklahoma Health Sciences	Oklahoma City	Oklahoma	United States	73104
27	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
28	Preferred Clinical Research	Pittsburgh	Pennsylvania	United States	15236
29	LeBonheur Children's Hospital	Memphis	Tennessee	United States	38105
30	Dallas Pediatric Neurology Associates	Dallas	Texas	United States	75230
31	Scott and White Healthcare	Temple	Texas	United States	76508
32	Primary Children's Medical Center	Salt Lake City	Utah	United States	84108
33	Eastern Virginia Medical School	Norfolk	Virginia	United States	23510
34	Seattle Children's Hospital	Seattle	Washington	United States	98105
35	Marshfield Clinic	Marshfield	Wisconsin	United States	54449

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Scott W. Powers, PhD, Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Andrew D. Hershey, MD, PhD, Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Christopher S. Coffey, PhD, University of Iowa

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01581281
• Other Study ID Numbers: CIN-001; 1U01NS076788-01
• First Posted: Apr 20, 2012
• Last Update Posted: Aug 10, 2017
• Last Verified: Jul 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Children's Hospital Medical Center, Cincinnati: Pediatric; Children; Adolescent; Headache; Migraine
• Additional relevant MeSH terms: Migraine Disorders; Headache; Topiramate; Amitriptyline

Study Results

Participant Flow

Recruitment Details	From July 16, 2012 through November 24, 2014, 488 patients were assessed for eligibility from 31 sites in the United States. Of those, 361 patients underwent randomization.
Pre-assignment Detail	Of the patients assessed for eligibility, 21 (4%) did not undergo randomization owing to early trial closure and 106 (22%) were excluded. Eighty-one (81) were excluded due to not meeting inclusion criteria, 25 declined participation (13 were unwilling, but eligibility was otherwise confirmed and 12 were willing and eligibility was unknown).

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Period Title: Overall Study
STARTED	145	72	144
COMPLETED	130	66	132
NOT COMPLETED	15	6	12

Baseline Characteristics

Arm/Group Title	Topiramate	Placebo	Amitriptyline	Total
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Total of all reporting groups
Overall Participants	145	72	144	361
Age (Count of Participants)
<=18 years	145 100%	72 100%	144 100%	361 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.2 (2.5)	14.2 (2.2)	14.2 (2.4)	14.2 (2.4)
Sex: Female, Male (Count of Participants)
Female	101 69.7%	49 68.1%	97 67.4%	247 68.4%
Male	44 30.3%	23 31.9%	47 32.6%	114 31.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 9.7%	6 8.3%	8 5.6%	28 7.8%
Not Hispanic or Latino	123 84.8%	65 90.3%	128 88.9%	316 87.5%
Unknown or Not Reported	8 5.5%	1 1.4%	8 5.6%	17 4.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	14 9.7%	5 6.9%	8 5.6%	27 7.5%
Asian	6 4.1%	0 0%	0 0%	6 1.7%
Native Hawaiian or Other Pacific Islander	1 0.7%	0 0%	0 0%	1 0.3%
Black or African American	24 16.6%	17 23.6%	26 18.1%	67 18.6%
White	98 67.6%	48 66.7%	107 74.3%	253 70.1%
More than one race	NA NaN	NA NaN	NA NaN	NA NaN
Unknown or Not Reported	2 1.4%	2 2.8%	3 2.1%	7 1.9%
Region of Enrollment (Count of Participants)
United States	145 100%	72 100%	144 100%	361 100%
Headache Days (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	11.5 (6.1)	11.0 (6.3)	11.5 (6.2)	11.4 (6.1)
Pediatric Migriane Disability Assessment Score (PedMIDAS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	42.6 (27.4)	42.9 (26.7)	40.6 (26.4)	41.9 (26.8)

Outcome Measures

1. Primary Outcome

Title	Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days
Description	The primary endpoint was a ≥ 50% reduction in headache frequency from the 28 days (4 weeks) baseline period prior to randomization to the last 28 days (4 weeks) of the trial. Headache frequency was defined as the number of days with headache for a given four week 28 day (4 week) period. A headache day was defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each participant, the primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period. Results were compared across the three treatment groups.
Time Frame	4 week baseline period and last 4 weeks of the 24-week trial

Outcome Measure Data

Analysis Population Description

The primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period between the participants receiving amitriptyline and participants receiving placebo.

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Measure Participants	130	66	132
Count of Participants [Participants]	72 49.7%	40 55.6%	69 47.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amitriptyline
	Comments	Logistic regression models were used to estimate the odds of successful primary endpoint for amitriptyline relative to placebo. The analyses followed the intention to treat principle, imputing an outcome of "failure" for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2636
	Comments	A Bonferroni approach was used to control the type I error rate. Because there were three comparisons, the Bonferroni corrected level of significance is 0.017 (= 0.05 / 3).
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 98.3%; 0.34 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Placebo
	Comments	Logistic regression models were used to estimate the odds of successful primary endpoint for topiramate relative to placebo. The analyses followed the intention to treat principle, imputing an outcome of "failure" for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4821
	Comments	A Bonferroni approach was used to control the type I error rate. Because there were three comparisons of interest, the Bonferroni corrected level of significance is 0.017 ( = 0.05 / 3).
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 98.3%; 0.39 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Amitriptyline
	Comments	Logistic regression models were used to estimate the odds of successful primary endpoint for topiramate relative to amitriptyline. The analyses followed the intention to treat principle, imputing an outcome of "failure" for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6107
	Comments	A Bonferroni approach was used to control the type I error rate. Because there were three comparisons of interest, the Bonferroni corrected level of significance is 0.017 ( = 0.05 / 3).
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 98.3%; 0.49 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Absolute Headache Disability Score on PedMIDAS
Description	The PedMIDAS scale which evaluated the impact of headaches in school, home, play, and social activities, is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions were answered by the youth in consultation with their parents and reviewed by study staff. The PedMIDAS scale was administered at baseline (covering the three months prior to enrollment) and at the 24-week endpoint visit (the end of the maintenance period, covering three months of enrollment). A total PedMIDAS score (sum of items 1-6) was used in this trial. Scores range from 0-240; with a score of 0-10 indicating no disability, 11-30 mild disability, 31-50 moderate disability, and more than 50 severe disability in daily activities. The main outcome measure for this comparison will be the difference in the baseline and endpoint (24 week) PedMIDAS total scores for: Amitriptyline vs. Placebo Topiramate vs. Placebo Amitriptyline vs Topiramate
Time Frame	baseline and 24 week endpoint

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Measure Participants	130	66	132
Mean (Standard Deviation) [units on a scale]	-26.8 (27.5)	-22.6 (29.42)	-22.5 (26.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amitriptyline
	Comments	The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9137
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -6.64 to 5.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Placebo
	Comments	The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1331
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-4.84
	Confidence Interval	(2-Sided) 95%; -11.16 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Amitriptyline
	Comments	The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1011
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.49
	Confidence Interval	(2-Sided) 95%; -0.88 to 9.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Number of Headache Days
Description	This outcomes measure examines whether the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This was assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. The change in absolute headache days was compared between: Amitriptyline vs. placebo Topiramate vs. placebo Amitriptyline vs. Topiramate
Time Frame	4 week baseline period and last 4 weeks of the 24-week trial

Outcome Measure Data

Analysis Population Description

The analysis population included all participants who had observed end-point data: 101 in the topiramate group, 59 in the placebo group, and104 in the amitriptyline group.

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Measure Participants	101	59	104
Mean (Standard Deviation) [days]	-6.7 (4.99)	-5.9 (6.96)	-6.7 (6.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amitriptyline
	Comments	Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3553
	Comments	Each comparison was tested using a Bonferroni corrected significance level of 0.017 (0.05/3).
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 98.3%; -2.59 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Placebo
	Comments	Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4143
	Comments	Each comparison was tested using a Bonferroni corrected significance level of 0.017 (0.05/3).
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 98.3%; -2.52 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Amitriptyline
	Comments	Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9038
	Comments	Each comparison was tested using a Bonferroni corrected significance level of 0.017 (0.05/3).
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 98.3%; -1.68 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase
Description	To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Tolerability was assessed for all participants included in the primary analysis. Of those randomized, 33 were not included in the primary analysis due to early trial closure.

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Measure Participants	130	66	132
Count of Participants [Participants]	102 70.3%	59 81.9%	106 73.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amitriptyline
	Comments	Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1557
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.07
	Confidence Interval	(2-Sided) 95%; 0.85 to 5.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Placebo
	Comments	Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0754
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.31
	Confidence Interval	(2-Sided) 95%; 0.95 to 5.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Amitriptyline
	Comments	Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7611
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Occurrence of Treatment Emergent Serious Adverse Events
Description	To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events.
Time Frame	24 weeks of the trial

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Topiramate	Placebo	Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.	Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).	Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
Measure Participants	145	72	144
Number [serious adverse events]	4	2	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Amitriptyline
	Comments	The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3038
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Placebo
	Comments	The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Topiramate, Amitriptyline
	Comments	The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2139
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Adverse events were collected after the ingestion of at least one dose of study drug through study completion, an average of 24 weeks.
Arm/Group Title	Topiramate		Placebo		Amitriptyline
Arm/Group Description	Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.		Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms).		Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved.
All Cause Mortality
	Topiramate		Placebo		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Topiramate		Placebo		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/145 (2.8%)		2/72 (2.8%)		6/144 (4.2%)
Gastrointestinal disorders
Intussusception	1/145 (0.7%)	1	0/72 (0%)	0	0/144 (0%)	0
Immune system disorders
Anaphylactic reaction	0/145 (0%)	0	0/72 (0%)	0	1/144 (0.7%)	1
Infections and infestations
Appendicitis	0/145 (0%)	0	1/72 (1.4%)	1	0/144 (0%)	0
Pharyngitis streptococcal	0/145 (0%)	0	1/72 (1.4%)	1	0/144 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/145 (0.7%)	1	0/72 (0%)	0	0/144 (0%)	0
Traumatic Liver Injury	1/145 (0.7%)	1	0/72 (0%)	0	0/144 (0%)	0
Nervous system disorders
Syncope	0/145 (0%)	0	0/72 (0%)	0	1/144 (0.7%)	1
Psychiatric disorders
Suicide attempt	1/145 (0.7%)	1	0/72 (0%)	0	0/144 (0%)	0
Mood altered	0/145 (0%)	0	0/72 (0%)	0	3/144 (2.1%)	3
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/145 (0%)	0	0/72 (0%)	0	1/144 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Topiramate		Placebo		Amitriptyline
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	111/145 (76.6%)		51/72 (70.8%)		106/144 (73.6%)
Gastrointestinal disorders
Dry Mouth	26/145 (17.9%)	30	9/72 (12.5%)	9	36/144 (25%)	45
General disorders
Fatigue	36/145 (24.8%)	40	10/72 (13.9%)	12	43/144 (29.9%)	48
Infections and infestations
Streptococcal Pharyngitis	1/145 (0.7%)	1	3/72 (4.2%)	3	7/144 (4.9%)	7
Upper Respiratory Tract Infection	18/145 (12.4%)	19	10/72 (13.9%)	10	14/144 (9.7%)	16
Investigations
Decreased Weight	11/145 (7.6%)	11	0/72 (0%)	0	0/144 (0%)	0
Nervous system disorders
Asphasia	23/145 (15.9%)	25	7/72 (9.7%)	9	13/144 (9%)	16
Cognitive Disorder	23/145 (15.9%)	25	8/72 (11.1%)	8	14/144 (9.7%)	18
Dizziness	9/145 (6.2%)	9	1/72 (1.4%)	2	3/144 (2.1%)	3
Memory Impairment	24/145 (16.6%)	29	7/72 (9.7%)	8	11/144 (7.6%)	11
Paresthesia	45/145 (31%)	67	6/72 (8.3%)	6	10/144 (6.9%)	10
Psychiatric disorders
Mood Altered	14/145 (9.7%)	16	4/72 (5.6%)	4	8/144 (5.6%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.